PROJECT SUMMARY/ABSTRACT Recent estimates suggest that almost two-thirds of the individuals diagnosed with Alzheimer?s disease [AD] are women. The National Institutes of Health and the Alzheimer?s Association have highlighted the critical need to understand sex differences in the risk factors and clinical progression of AD. Reproductive and hormonal factors may be particularly important for women. Hypertensive pregnancy disorders [HPD] have been associated with subjective cognitive complaints or white matter lesions five to ten years after the HPD, but the long-term effects of HPD on brain structure and cognitive function are unknown. Population-based studies are needed to assess the contribution of HPD and subtype (i.e., preeclampsia) to the risk of cognitive decline, AD, and neuroimaging measures of amyloid-beta [A?], neurodegeneration, and cerebrovascular pathologies. Further, observational studies and clinical trials have examined the effects of early menopause (natural or surgically-induced) and hormonal therapy [HT] on the risk of AD and other dementias. However, it is not currently known whether the effects of early menopause, HT use, and their interactions with APOE genotype, are associated with specific type(s) of brain pathology (i.e., A?, neurodegeneration, cerebrovascular) because multi-modal imaging studies have not been conducted. The overall aims of this proposal are to elucidate the impact of two hormonally-related sex-specific factors for women, pregnancy (e.g., number of pregnancies, HPD) and menopause (surgically-induced or natural), on the risk of cognitive decline, AD, and neuroimaging measures of A?, neurodegeneration, and cerebrovascular pathologies. Because the literature and our preliminary data suggest that risk scores for cardiovascular disease and dementia are less predictive in women compared to men, we also propose to incorporate these sex-specific factors to develop a more predictive risk score of mild cognitive impairment and AD for women. To accomplish our goals, we will utilize two existing infrastructures at the Mayo Clinic: the Mayo Clinic Study of Aging (MCSA; U01 AG006786) and the Rochester Epidemiology Project medical records-linkage system (REP; R01 AG034676). Using the REP, we will newly abstract information on pregnancy and menopause for 2,370 women enrolled in the MCSA. Because few studies assessing pregnancy and menopause have also adjusted for putative confounding variables, we will also abstract this data using the REP to determine whether these sex-specific conditions are independent predictors of cognitive decline, AD, and neuroimaging measures of specific brain pathologies. Successful completion of these aims will be a key step towards understanding whether these sex-specific factors are associated with the risk of AD in women, to understanding whether these factors are related to a specific type of brain pathology (i.e., A?, neurodegeneration, cerebrovascular), and to developing a better risk score for predicting cognitive impairment, dementia, and specific brain changes in women.